Several clinical findings suggest that schizophrenia may involve improper functioning of the prefrontal cortex. Two basic assumptions are made in this application: (1) the proposed prefrontal cortex malfunction may alter the excitatory amino acid neurotransmission of prefrontal cortex efferents and (2) chronic antipsychotic drug treatment may exert some of its effects by acting on excitatory amino acid transmission through its interaction with midbrain dopamine systems. These assumptions are in part based on the clinical findings that have pointed to prefrontal cortical hypometabolism in schizophrenic patients during performance of frontal lobe tasks and our preliminary data indicating that the basal extracellular concentration of the putative excitatory amino acid transmitter, 1-glutamate, is significantly higher in animals that have been treated chronically with the antipsychotic drug haloperidol. The goals of the proposed experiments are to enhance our understanding of the basic biochemical characteristics of prefrontal cortex excitatory efferents and their interaction with subcortical dopamine systems, which are thought to be important sites for the action of antipsychotic drugs. Specifically, the following questions are addressed: (1) What are the basic release characteristics of excitatory amino acid. For example, do excitatory amino acid presynaptic receptors modulate their, own release? (2) How do excitatory amino acids and dopamine modulate each others function in subcortical areas. (3) How does treatment with antipsychotic drugs affect release characteristics of excitatory amino acids in the above regions and finally, (4) How does a decrease in prefrontal cortex neurotransmission alter the release characteristics of excitatory amino acids and dopamine in subcortical areas? The technique of in vivo microdialysis in conscious rats along with complementary in vivo and in vitro biochemical techniques will be utilized to perform the above experiments.